ITR: Collaborative Research: (ASE+NHS+EVS)-(sim+dmc+int): In Silico De Novo Protein Design: A Dynamically Data Driven, (DDDAS), Computational and Experimental Framework

研究：计算机蛋白质设计中的一个挑战是发现与目标模板结构或任意三维结构兼容的新蛋白质。这项研究是一个动态数据驱动的应用系统(DDDAS)，通过一个综合的研究框架(即计算、物理化学和生化方法)来进行多肽和蛋白质的电子从头设计。该项目的主要目标是(I)通过基于混合整数优化和确定性全局优化的新型计算框架进行电子序列选择和折叠特异性计算，(Ii)通过核磁共振、结构确定和分子动力学进行体外和电子表征，(Iii)预测序列的蛋白质表达、结构表征和活性测量，以及(Iv)开发一个网络工作台支持系统，用于从头开始的多肽/蛋白质设计，所有研究人员都可以免费获得。用于测试和验证建议框架的生物系统包括C3a过敏性毒素(AIMS(I)-(IV))和人β防御素(AIMS(I)，分子动力学(II)和(IV))。智力优势：计划中的工作涉及来自三个机构(普林斯顿大学、宾夕法尼亚大学、加州大学河滨分校)的跨学科团队(弗洛达斯、兰布里斯、莫里基斯)。他们的专业知识涵盖补体生物学、蛋白质化学、结构生物学、数学建模和分析、组合和全局优化、科学计算和生物工程等领域，该项目是一项综合计算和实验工作。这些发展可以大大加快药物发现进程，解决新药设计中的重要任务，拟议的基于网络的工作台的新概念将是对科学界的第一次这样的服务。更广泛的影响：使用IT和DDDAS技术，在一个独特的共生计算和实验框架中，该项目将为在新药发现方面取得重大进展奠定基础。这种电子预测新序列的框架选择性地折叠成结构模板并进行实验验证，将允许快速筛选新的替代品，并将导致更好、更快的药物发现，这将对我们的社会产生直接影响。拟议的努力将研究生、博士后和本科生的参与整合到研究中，从而提供了多学科培训机会。作为初级独立工作和高级论文工作的一部分，联合PIs有与本科生进行研究的记录。这三家机构都有吸引传统上代表性不足群体的学生和员工的政策。联合PIS致力于与这些学生合作，并将积极努力，吸引他们参加这个研究项目、系列研讨会、期刊俱乐部和研究生水平的课程。合作私人投资机构在培养本科生和研究生以及来自代表性不足群体的博士后助理方面有着良好的记录。研究结果将通过档案期刊上的出版物、参考会议记录和在会议上的陈述向整个科学界传播。此外，开发基于网络的多肽/蛋白质从头设计工作台将首次为科学界提供服务。

ABSTRACTPI: Dimitrios Morikis Institution: University of California RiversideProposal Number: 0427103Research: A challenge in computational protein design is the discovery of novel proteins, which are compatible with either target template structures or arbitrarily three dimensional structures. This research is a dynamically data driven application systems, (DDDAS), effort through an integrative research framework, (i.e., computational, physicochemical, and biochemical approaches) for the in silico de novo design of peptides and proteins. The primary aims of the project are (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, (iii) protein expression, structural characterization and activity measurements of predicted sequences, and (iv) the development of a web-based WorkBench support system for de novo peptide/protein design which will be freely available to all researchers. The biological systems for testing and validating the proposed framework include the C3a anaphylatoxin (aims (i)-(iv)), and human beta defensins (aims (i), molecular dynamics of (ii) and (iv)). Intellectual Merit:The planned effort involves an interdisciplinary team (Floudas, Lambris, Morikis) from three institutions (Princeton, U. Penn, U. California at Riverside). Their expertise spans the fields of complement biology, protein chemistry, structural biology, mathematical modeling and analysis, combinatorial and global optimization, scientific computing, and bioengineering, and the project is an integrative computational and experimental effort. These developments can expedite significantly the drug discovery process, address important tasks in the design of new drugs, and the proposed novel concept of a web-based WorkBench will be the first such service to the scientific community. Broader Impacts: Using IT and DDDAS techniques, in a uniquely symbiotic computational and experimental framework, this project will lay the groundwork for making significant advances in the discovery of new drugs. This framework for in silico prediction of new sequences which fold selectively to structural templates and their experimental validation will allow rapid screening of novel alternatives and will lead into better and faster drug discovery which has direct impact in our society. The proposed effort integrates participation of graduate students, postdoctoral students, and undergraduate students into the research, thereby providing multidisciplinary training opportunities. The co-PIs have records in research with undergraduate students as part of their junior independent work, as well as senior thesis work. All three institutions have policies for attracting students and employees from traditionally under-represented groups. The co-PIs are committed to working with these students and will work pro-actively to attract them to this research project, the seminar series, the journal club, and the graduate level course. The co-PIs have strong records of educating undergraduate and graduate students, and post-doctoral associates from under-represented groups. The results of the research will be disseminated to the entire scientific community through publications in archival journals, refereed proceedings, and via presentations at conferences. Furthermore, the development of the web-based WorkBench for the de novo design of peptide/proteins will provide, for the first time, service to the scientific community.